近期发病的幼年特发性关节炎的亚型特异性外周血基因表达谱

Subtype-specific peripheral blood gene expression profiles in recent-onset juvenile idiopathic arthritis.

作者信息

Barnes Michael G, Grom Alexei A, Thompson Susan D, Griffin Thomas A, Pavlidis Paul, Itert Lukasz, Fall Ndate, Sowders Dawn Paxson, Hinze Claas H, Aronow Bruce J, Luyrink Lorie K, Srivastava Shweta, Ilowite Norman T, Gottlieb Beth S, Olson Judyann C, Sherry David D, Glass David N, Colbert Robert A

机构信息

Division of Pediatric Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.

出版信息

Arthritis Rheum. 2009 Jul;60(7):2102-12. doi: 10.1002/art.24601.

DOI:10.1002/art.24601

PMID:19565513

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2782469/

Abstract

OBJECTIVE

To identify differences in peripheral blood gene expression between patients with different subclasses of juvenile idiopathic arthritis (JIA) and healthy controls in a multicenter study of patients with recent-onset JIA prior to treatment with disease-modifying antirheumatic drugs (DMARDs) or biologic agents.

METHODS

Peripheral blood mononuclear cells (PBMCs) from 59 healthy children and 136 patients with JIA (28 with enthesitis-related arthritis [ERA], 42 with persistent oligoarthritis, 45 with rheumatoid factor [RF]-negative polyarthritis, and 21 with systemic disease) were isolated from whole blood. Poly(A) RNA was labeled using a commercial RNA amplification and labeling system (NuGEN Ovation), and gene expression profiles were obtained using commercial expression microarrays (Affymetrix HG-U133 Plus 2.0).

RESULTS

A total of 9,501 differentially expressed probe sets were identified among the JIA subtypes and controls (by analysis of variance; false discovery rate 5%). Specifically, 193, 1,036, 873, and 7,595 probe sets were different in PBMCs from the controls compared with those from the ERA, persistent oligoarthritis, RF-negative polyarthritis, and systemic JIA patients, respectively. In patients with persistent oligoarthritis, RF-negative polyarthritis, and systemic JIA subtypes, up-regulation of genes associated with interleukin-10 (IL-10) signaling was prominent. A hemoglobin cluster was identified that was underexpressed in ERA patients but overexpressed in systemic JIA patients. The influence of JAK/STAT, ERK/MAPK, IL-2, and B cell receptor signaling pathways was evident in patients with persistent oligoarthritis. In systemic JIA, up-regulation of innate immune pathways, including IL-6, Toll-like receptor/IL-1 receptor, and peroxisome proliferator-activated receptor signaling, were noted, along with down-regulation of gene networks related to natural killer cells and T cells. Complement and coagulation pathways were up-regulated in systemic JIA, with a subset of these genes being differentially expressed in other subtypes as well.

CONCLUSION

Expression analysis identified differentially expressed genes in PBMCs obtained early in the disease from patients with different subtypes of JIA and in healthy controls, providing evidence of immunobiologic differences between these forms of childhood arthritis.

摘要

目的

在一项针对近期发病、尚未接受改善病情抗风湿药物（DMARDs）或生物制剂治疗的幼年特发性关节炎（JIA）患者的多中心研究中，确定不同亚型JIA患者与健康对照者外周血基因表达的差异。

方法

从59名健康儿童和136例JIA患者（28例附着点炎相关关节炎[ERA]、42例持续性寡关节炎、45例类风湿因子[RF]阴性多关节炎和21例全身型疾病患者）的全血中分离外周血单个核细胞（PBMC）。使用商业RNA扩增和标记系统（NuGEN Ovation）对poly(A) RNA进行标记，并使用商业表达微阵列（Affymetrix HG-U133 Plus 2.0）获得基因表达谱。

结果

在JIA亚型和对照者中总共鉴定出9501个差异表达的探针集（通过方差分析；错误发现率5%）。具体而言，与对照者相比，ERA、持续性寡关节炎、RF阴性多关节炎和全身型JIA患者的PBMC中分别有193、1036、873和7595个探针集存在差异。在持续性寡关节炎、RF阴性多关节炎和全身型JIA亚型患者中，与白细胞介素-10（IL-10）信号相关的基因上调显著。鉴定出一个血红蛋白簇，其在ERA患者中表达不足，但在全身型JIA患者中过度表达。JAK/STAT、ERK/MAPK、IL-2和B细胞受体信号通路的影响在持续性寡关节炎患者中明显。在全身型JIA中，观察到包括IL-6、Toll样受体/IL-1受体和过氧化物酶体增殖物激活受体信号在内的固有免疫通路上调，同时与自然杀伤细胞和T细胞相关的基因网络下调。补体和凝血通路在全身型JIA中上调，其中一部分基因在其他亚型中也有差异表达。